Oral immunotherapy suppresses peripheral blood transcriptomic response to peanut in peanut allergy

Peanut allergy is a common condition without a cure. Oral immunotherapy (OIT) induces desensitization, but its mechanisms are not fully understood.

We sought to characterize how OIT alters the peripheral blood transcriptome in peanut allergy.

We studied peripheral blood transcriptomes as 73 children aged 4 to 14 years with high-threshold peanut allergy received OIT or avoided peanut in a randomized trial. Participants randomized to OIT (n = 38) ingested peanut daily, with the dose increased every 8 weeks until they reached 3396 mg or 72 weeks had passed. Participants randomized to avoidance (n = 35) avoided peanut for equivalent periods. Double-blind, placebo-controlled food challenges were conducted at baseline, after treatment, and after OIT cessation. Peripheral blood samples were collected at all double-blind, placebo-controlled food challenges. Sequencing of peripheral blood RNA, statistical analyses, and machine learning were performed.

The entire OIT group (100%) achieved desensitization compared with 21% in the avoidance group. With peanut exposure, OIT-treated participants demonstrated marked suppression of a 295-transcript signature representing neutrophil degranulation and IL-4 and IL-13 signaling. Machine learning identified 27 transcripts that classified OIT-induced desensitization in independent participants with 80% accuracy. Highly ranked transcript classifiers included FOS, NDST1, LTB4R, and IER. These transcripts remained suppressed after OIT cessation. Lower levels of these transcripts were also observed in non-peanut-allergic individuals.

OIT markedly suppressed transcriptional processes triggered by peanut exposure, paralleling clinical desensitization, and persisting after OIT cessation. Machine learning prioritized 27 transcripts that classified OIT-induced desensitization with high accuracy. These findings advance mechanistic understanding of OIT and point to potential therapeutic targets for peanut allergy.